Cachexia, a wasting disease characterized by progressive loss of muscle with or without loss of fat mass, is frequently associated with cancer and is estimated to be the immediate cause of death in 20% to 40% of cancer patients. The prominent clinical feature of cachexia is weight loss, along with anorexia, inflammation, insulin resistance, and increased muscle protein breakdown. However, due to the poor understanding of its etiology there is currently no FDA-approved treatment for cancer-induced cachexia. Based on existing data, we postulate that fast growing tumors sustain high-level protein synthesis by releasing factors to extract amino acids from skeletal muscle via stimulating proteolysis, which is mediated by the systems that govern cellular protein degradation. However, the identities of the key tumor cell-release factors that induce the catabolic actions remain elusive. In preliminary studies, we found that a number of cachectic tumor cells constitutively release specific heat shock proteins (HSPs), which appear to be critical agents in tumor-induced cachexia. Traditionally, HSPs are primarily known as intracellular molecular chaperones for protein folding, assembly, and translocation, thus making them cytoprotective. Recently, HSPs have been shown being released by certain cells, including tumor cells, into the extracellular space where they play a major role in intercellular crosstalk. Tumor cell-released HSPs have been shown to elicit inflammatory responses via immune cells and promote metastasis. Importantly, high serum level of HSP associates with the high mortality in patients with colorectal and lung cancer, of which cachexia is often the immediate cause of death. However, the effects of extracellular HSPs on muscle cells are unknown. Preliminary data suggest that tumor cell- released HSPs are crucial for tumor-induced muscle catabolism by acting directly on muscle cells to activate the cellular protein degradation systems. We propose to evaluate the role of tumor-released HSPs in the development of cachexia, utilizing cellular and molecular approaches, in cell culture and mouse models of cancer cachexia. Three specific aims will be pursued: 1) to evaluate the contribution of tumor cell-released HSPs to cachexia; 2) to elucidate the signaling mechanism through which extracellular HSPs induce muscle catabolism; and 3) to determine the mechanism of constitutive release of HSPs by tumor cells. Success of the current project would establish a new paradigm for the etiology and treatment of cancer cachexia. Despite the fact that cachexia affects about 50% of cancer patients, it is essentially left untreated. By understanding the role of extracellular HSPs in cancer cachexia through the proposed studies above, treatment of cancer cachexia in humans could be tested in the short-term by utilizing reagents that have already been approved by the FDA for human use or clinical trials that inhibit HSPs, their membrane receptors and intracellular signaling pathways, or their release from tumor cells.